Affective disorders are a host of psychiatric conditions that have a disturbance in mood as their predominant feature. These are for example depression, bipolar disorder (also known as manic depression), dysthymia, and cyclothymia.
A bipolar disorder is a form of a depressive disease that characteristically involves cycles of depression and elation or mania. Sometimes the mood switches from high to low and back again are dramatic and rapid switches, but more often they are gradual and slow.
Both phases of the disease are deleterious. Mania affects thinking, judgment, and social behavior in ways that may cause serious problems and embarrassment. For example, unwise business or financial decisions may be made when an individual is in a manic phase. Depression can also affect thinking, judgment, and social behavior in ways that may cause grave problems. For example, it raises the risk of suicide. Bipolar disorder is not as prevalent as some other forms of depressive disorders but it is often a chronic recurring condition.
Valproic acid (VPA) is one of the major antiepileptic drugs used today, having a wide use in both generalized and partial epilepsies. Valproic acid is a leading mood stabilizer for the treatment of bipolar disorder. Its well-known teratogenicity limits its use in young women of childbearing age.
The use of VPA is limited by its considerable adverse effects including hepatotoxicity and teratogenicity and thus cannot be given to women of childbearing age and children [Baille, T. A. et al. In Antiepileptic Drugs, eds. R. H. Levy et al. Raven Press, New York. Pp. 641-651 (1989)].
There is thus a widely recognized need for, and it would be highly advantageous to have, new agents for treating bipolar disorder devoid of the above limitations.
Valnoctamide (VCD), an amide analogue of VPA having anti-convulsant activity was found to be distinctly less teratogenic than VPA [Radatz M et al. Epilepsy Res. 1998:30(1):41-8]. Roeder et al [M. Roeder et al, Tetrahedron: Asymmetry 1999: 10: 841-853] and U.S. Pat. No. 6,417,399 relate to stereoisomers of valnoctamide (VCD), synthesis thereof, a method for stereoselective separation thereof as well as uses thereof. The '399patent is directed to the sterioisomers and does not disclose the racemic mixture. Furthermore this application does not address specifically bipolar disorder
WO 99/54282 discloses compounds for the treatment, among other of affective disorders. This application does not mention explicitly racemic VCD nor does it mention its use in the treatment of bipolar disorders.
U.S. Pat. No. 5,880,157 and Bialer et al. [M. Bialer et al. Pharm Res. 13: 284-289 (1996)] disclose derivatives of 2,2,3,3 tetramethylcyclopropane carboxylic acid for treating epilepsy. Isoherranen et al 2002 studied the anticonvulsant activity of N-methyl-tetramethylcyclopropyl carboxamide (M-TMCD) and its metabolite in various animal (rodent) models of human epilepsy, and evaluated their ability to induce neural tube defects (NTDs) and neurotoxicity [Isoherranen N. et al. Epilepsia 2002; 43:115-126]. M-TMCD (a cyclopropyl analog of VPA) was found to be advantageous compared to VPA because of its better potency as an anticonvulsant drug, its wider safety of margin, its lack of teratogenicity and its potential lack of hepatotoxicity.
Thus, there is a widely recognized need and it will be highly advantageous to have compounds which are effective in treating bipolar disorders with minimal side effects.